Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts
Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts
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DOI：
10.1093/hmg/ddh291
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发表时间：
2004-11-01
影响因子：
3.5
通讯作者：
Estévez, R
中科院分区：
文献类型：
--
作者：
Teijido, O;Martínez, A;Estévez, R
MLC 1基因的突变导致一种神经系统疾病--巨脑白质脑病伴皮质下囊肿（MLC）。这种疾病是一种空泡性髓鞘病。MLC 1蛋白的生物化学性质和功能尚不清楚。为了表征MLC 1，我们产生了多克隆抗体。MLC 1蛋白在大脑中被检测到，组装成更高的分子复合物，通过组装依赖性运输试验进行评估。原位杂交和免疫组织化学被用来确定MLC 1定位在成年小鼠脑内。MLC 1在神经元中表达，在特定的轴突束中优先检测。这种表达模式与疾病中观察到的主要表型相关。此外，它在一些星形胶质细胞中表达，集中在Bergmann胶质细胞、邻近血管的星形胶质细胞终足膜和星形胶质细胞-星形胶质细胞膜接触区。其他神经元屏障，如室管膜和软脑膜，MLC 1表达也呈阳性。MLC 1在体内和异源系统中在质膜上检测到。MLC突变损害折叠，并通过添加姜黄素（一种Ca 2 +-ATP酶抑制剂）在体外纠正缺陷。总之，这项研究解释了为什么MLC 1突变会引发这种疾病，并为一些患者提供了可能的治疗方法。
Mutations in the MLC1 gene are responsible for one form of the neurological disorder megalencephalic leukoencephalopathy with subcortical cysts (MLC). The disease is a type of vacuolating myelinopathy. The biochemical properties and the function of the MLC1 protein are unknown. To characterize MLC1, we generated polyclonal antibodies. The MLC1 protein was detected in the brain, assembled into higher molecular complexes, as assessed by assembly-dependent trafficking assays. In situ hybridization and immunohistochemistry were used to determine MLC1 localization within the adult mouse brain. MLC1 was expressed in neurons, detected preferentially in particular axonal tracts. This expression pattern correlates with the major phenotype observed in the disease. In addition, it was expressed in some astrocytes, concentrating in Bergmann glia, the astrocyte end-feet membranes adjacent to blood vessels and in astrocyte-astrocyte membrane contact regions. Other neuronal barriers, such as the ependyma and the pia mater, were also positive for MLC1 expression. MLC1 was detected in vivo and in heterologous systems at the plasma membrane. MLC mutations impaired folding, and the defect was corrected in vitro by addition of curcumin, a Ca2+-ATPase inhibitor. In summary, this study provides an explanation as to why mutations in MLC1 provoke the disease and points to a possible therapy for some patients.